Our laboratory is interested in the role of endogenous protease inhibitors in normal cellular homeostasis and in proliferative diseases such as neoplasia. We
are particularly keen in understanding the role of the cysteine protease inhibitors
known as cystatins (CSTs) in cell proliferation, differentiation and senescence. There are a dozen distinct
cystatins in mammals. In the test tube, these cystatins behave like potent inhibitors
of lysosomal cysteine proteases such as the cathepsins B, H, K, L and S. Due to the reversible nature of the interaction of cystatins with cathepsins it
has been difficult to demonstrate the formation of enzyme-inhibitor complexes in situ.
Moreover, cystatins – particularly secreted cystatins - seem to have acquired additional
functions in cell and tissue homeostasis. Indeed, cystatins have been implicated in
many important biological processes, such as cell survival, proliferation, migration,
differentiation, senescence and modulation of immune function. Therefore, an important
challenge of the research in this field is to determine their precise enzyme targets.
The short-term goal of our endeavors is to define to what extent inhibition of peri- or intracellular
proteases is responsible for the cystatin's multiple biological functions. Thelong-term goal is to move this research into the clinical arena where cystatin-derived reagents
can be tested for their efficacy as novel diagnostic/prognostic tools or therapeutic
agents.

Currently, we are pursuing three projects:

1. Role of CST1 as a novel gene induced during cellular senescence. Expression, secretion, localization
and role on neighboring cells and tissues. Role of CST1 (and the gene product Cst-1/cystatin SN) as a novel biomarker of cellular senescence.

2. Role of CST6 as a novel tumor suppressor gene. Expression, secretion, localization and role during
early tumor formation and progression.

3. Role of CST3 in cell survival and proliferation. Identification and characterization of a potential
cell surface cystatin-binding/receptor molecule

Research on cystatins provides an excellent environment for the motivation and training
of young scientists. This research has also great potential for translational applications
and drug development. Indeed, cystatins have been implicated in embryonic stem cell
proliferation and differentiation as well as in progression of age-associated diseases
such as neurodegenerative, cardiovascular and malignant diseases.